We have evidence using two methods developed in our laboratory that sera of breast cancer patients have cross-reacting antibodies to mouse mammary tumor virus (MuMTV). The antibody levels are reduced by more than 80% following absorption with MuMTV, the membrane protein of the virus gp52, and also in preliminary experiments, by deglycosylated virus, indicating that the antibody is not a heterophile. Further, the antibody is not absorbable by erythrocytes from equine, human, sheep, bovine and pig, fetal calf serum and by two murine leukemia viruses (AKR and Rauscher). Studies from a geographical perspective show that 66% of women with breast cancer from E. Africa, 26% from U.S. and 31% of E. Indian women have this antibody in their sera. In contrast, only 5% of Chinese women with breast cancer have this antibody. Studies of families with a high propensity for breast cancer showed that family members including some male members also have this antibody. We have also demonstrated that breast cyst fluids (BCF) have an IgA antibody with reactivity to MuMTV. We plan to investigate the specificity of this antibody present in serum of some breast cancer patients using exhaustive and extensive absorptions and inhibition assays. We will also search for the antigen(s) to the MuMTV free in the circulation and in circulating immune complexes (CICs) in sera of patients with breast cancer using monospecific antisera against MuMTV, gp52, monoclonal antibodies, deglycosylated MuMTV. We will search for free antibody in serum and in CICs using purified MuMTV and all defined components of MuMTV. We will apply these reagents to study the relationship of the antibody in sera of breast cancer patients and the presence of antigens recognized by antibodies to the MuMTV in breast tissue from the same patients, and to study particles present in breast cyst fluid and breast nipple expression. Preliminary data in our laboratory show that high levels of CICs correlate with low levels of MuMTV-reactive antibody and complement. Following mastectomy, the CIC levels drop, antibody and complement levels increase. These studies, using new methodologies and new materials (BCF), will allow for a clearer definintion of the relationship between MuMTV and human breast cancer.